Characteristics of Recurrent Ischemic Stroke After Embolic Stroke of Undetermined Source: Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: The concept of embolic stroke of undetermined source (ESUS) unifies a subgroup of cryptogenic strokes based on neuroimaging, a defined minimum set of diagnostic tests, and exclusion of certain causes. Despite an annual stroke recurrence rate of 5%, little is known about the etiology underlying recurrent stroke after ESUS.

Objective: To identify the stroke subtype of recurrent ischemic strokes after ESUS, to explore the interaction with treatment assignment in each category, and to examine the consistency of cerebral location of qualifying ESUS and recurrent ischemic stroke.

Design, setting, and participants: The NAVIGATE-ESUS trial was a randomized clinical trial conducted from December 23, 2014, to October 5, 2017. The trial compared the efficacy and safety of rivaroxaban and aspirin in patients with recent ESUS (n = 7213). Ischemic stroke was validated in 309 of the 7213 patients by adjudicators blinded to treatment assignment and classified by local investigators into the categories ESUS or non-ESUS (ie, cardioembolic, atherosclerotic, lacunar, other determined cause, or insufficient testing). Five patients with recurrent strokes that could not be defined as ischemic or hemorrhagic in absence of neuroimaging or autopsy were excluded. Data for this secondary post hoc analysis were analyzed from March to June 2019.

Interventions: Patients were randomly assigned to receive rivaroxaban, 15 mg/d, or aspirin, 100 mg/d.

Main outcomes and measures: Association of recurrent ESUS with stroke characteristics.

Results: A total of 309 patients (205 men [66%]; mean [SD] age, 68 [10] years) had ischemic stroke identified during the median follow-up of 11 (interquartile range [IQR], 12) months (annualized rate, 4.6%). Diagnostic testing was insufficient for etiological classification in 39 patients (13%). Of 270 classifiable ischemic strokes, 156 (58%) were ESUS and 114 (42%) were non-ESUS (37 [32%] cardioembolic, 26 [23%] atherosclerotic, 35 [31%] lacunar, and 16 [14%] other determined cause). Atrial fibrillation was found in 27 patients (9%) with recurrent ischemic stroke and was associated with higher morbidity (median change in modified Rankin scale score 2 [IQR, 3] vs 0 (IQR, 1]) and mortality (15% vs 1%) than other causes. Risk of recurrence did not differ significantly by subtype between treatment groups. For both the qualifying and recurrent strokes, location of infarct was more often in the left (46% and 54%, respectively) than right hemisphere (40% and 37%, respectively) or brainstem or cerebellum (14% and 9%, respectively).

Conclusions and relevance: In this secondary analysis of randomized clinical trial data, most recurrent strokes after ESUS were embolic and of undetermined source. Recurrences associated with atrial fibrillation were a minority but were more often disabling and fatal. More extensive investigation to identify the embolic source is important toward an effective antithrombotic strategy.

Trial registration: ClinicalTrials.gov Identifier: NCT02313909.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Veltkamp reported receiving fees for consulting and speaker honoraria from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Inc, Daiichi Sankyo Company, Limited, Portola Pharmaceuticals, Biogen, Inc, Medtronic plc, MorphoSys AG, Amgen, Inc, and Javelin Biotech and research support from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Inc, Daiichi Sankyo Company, Limited, Medtronic plc, and Biogen Inc outside of present work; and serving as an investigator of Imperial Biomedical Research Center and partially funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement 754517 (PRESTIGE-AF). Dr Korompoki reported receiving speaker fees, serving on the advisory board, and receiving travel grants from Amgen, Inc, Bayer AG, and Bristol-Myers Squibb and Pfizer, Inc, outside the submitted work. Dr Sharma reported receiving research support from Bayer AG, Bristol-Myers Squibb, and Boehringer Ingelheim and serving on the advisory board and/or receiving speaker’s honoraria from Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, and Daiichi Sankyo Company, Limited. Dr Kasner reported receiving research support from Bayer AG, Bristol-Myers Squibb, WL Gore and Associates, and Medtronic plc and consulting for Bristol-Myers Squibb, Boehringer Ingelheim, and Portola Pharmaceuticals. Dr Toni reported receiving speaker fees or serving on the advisory board of Abbott Laboratories, Boehringer Ingelheim, Bayer AG, Daiichi Sankyo Company, Limited, Medtronic plc, and Pfizer, Inc. Dr Ameriso reported receiving speaker fees, serving on steering committees, and receiving travel grants and clinical research honorarium from Bayer AG, Boehringer Ingelheim, and Bristol-Myers Squibb/Pfizer, Inc. Dr Tatlisumak reported serving on the advisory board of Bayer AG, Boehringer Ingelheim, Brainsgate, Bristol-Myers Squibb, Lumosa Pharma, Inc, and Portola Pharmaceuticals and receiving research contracts with Bayer AG, Boehringer Ingelheim, Brainsgate, Pfizer, Inc, Portola Pharmaceuticals, and Sanofi Aventis. Dr Hankey reported receiving personal honoraria outside the submitted work from Bayer AG, Bristol-Myers Squibb, Medscape, and the American Heart Association. Dr Lindgren reported receiving grants from the Swedish Heart and Lung Foundation, Region Skåne, Skåne University Hospital, Freemasons Lodge of Instruction Eos in Lund, Lund University, and the Foundation of Färs & Frosta (one of Sparbanken Skåne’s ownership foundations) and personal fees from Bayer AG, AstraZeneca plc, Bristol-Myers Squibb/Pfizer, Inc, and Portola Pharmaceuticals outside the submitted work. Dr Arauz reported receiving speaker fees, serving on steering committees, and receiving travel grants from Bayer AG, Boehringer Ingelheim, and Pfizer, Inc. Dr Muir reported receiving honoraria outside the submitted work from Bayer AG, Daiichi Sankyo Company, Limited, Boehringer Ingelheim and research support from Boehringer Ingelheim. Dr Perera reported receiving speaker fees and research grants and serving on advisory boards from Bayer AG and speaker fees from Abbott Laboratories. Dr Shoamanesh reported receiving research support and honoraria from Bayer AG. Dr Connolly reported receiving research funding and consulting honoraria from Bayer AG, Bristol-Myers Squibb, Daiichi Sankyo Company, Limited, Portola Pharmaceuticals, Javelin Biotech, and Boehringer Ingelheim. Dr Hart reported receiving a stipend for research and honoraria for advisory board participation from Bayer AG. No other disclosures were reported.

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Figure.. Trial Profile